Atypical antipsychotics are widely prescribed to millions of people in the United States for treatment of schizophrenia, bipolar disorder and other psychiatric conditions. Evidence has been accumulating that these drugs often cause substantial weight gain and fasting hyperglycemia, and may confer increased risk for overt diabetes and life-threatening diabetic ketoacidosis. Weight gain is a known risk factor for diabetes, especially if increased weight reflects increase in visceral obesity, but drug-associated diabetes has occurred in the absence of, or develop prior to drug-related obesity. While these drugs may place many people at risk for diabetes, little is known about the mechanisms by which metabolism becomes altered by these drugs and obesity and diabetes develops. We have observed that chronic administration of two commonly prescribed drugs to normal dogs causes significant metabolic disturbances, including obesity, but diabetes did not develop. We propose to test the hypothesis that antipsychotics cause diabetes by inducing metabolic derangements over a backdrop of enhanced risk for the disease, such as that conferred by schizophrenia in the absence of pharmacologic intervention. Drugs will be given to dogs in which diabetic risk factors have been induced - specifically, modest insulin secretory defect or visceral adiposity resulting from high fat diet - to test whether that drug-induced development of frank diabetes would develop in dogs with known risk factors for the disease. We also propose studies to determine the mechanism by which these drugs cause weight gain. We will test whether increased caloric intake can account for all weight gain, or whether drugs act to decrease energy expenditure, either under basal resting conditions or by reducing energy output associated with physical activity. Finally, although the brain is the obvious site of the psychotropic action of atypical antipsychotics, the target tissues which mediate the metabolic disturbances caused by these drugs is not known. We propose a series of studies to determine whether atypical antipsychotics act via central or peripheral mechanisms to induce obesity, hepatic insulin resistance, and diminished pancreatic a-cell function. Studies of the metabolic effects of these agents are critical to understand the increased risk of diabetes in patients undergoing treatment with psychotropic medication.